ClinVar Miner

Submissions for variant NM_001033855.3(DCLRE1C):c.180C>A (p.Tyr60Ter)

dbSNP: rs2131108640
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen RCV001905270 SCV004242287 likely pathogenic Severe combined immunodeficiency due to DCLRE1C deficiency 2024-01-23 reviewed by expert panel curation The NM_001033855.3:c.180C>A (p.Tyr60Ter) variant in DCLRE1C is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon, 3/14, which is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The highest population minor allele frequency in gnomAD v4 is 0.000001313 (1/761794 alleles) in the European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, meeting this criterion (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting and PVS1 (VCEP specifications version 1).
Labcorp Genetics (formerly Invitae), Labcorp RCV001905270 SCV002133432 pathogenic Severe combined immunodeficiency due to DCLRE1C deficiency 2021-07-02 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr60*) in the DCLRE1C gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DCLRE1C are known to be pathogenic (PMID: 21664875, 26123418).

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